Protein phosphatase 2A has an essential role in promoting thymocyte survival during selection

• Published in: Proceedings of the National Academy of Sciences - PNAS 2019-06, Vol.116 (25), p.12422-12427
• Main Authors: Zheng, Mingzhu, Li, Dan, Zhao, Zhishan, Shytikov, Dmytro, Xu, Qin, Jin, Xuexiao, Liang, Jingjing, Lou, Jun, Wu, Songquan, Wang, Lie, Hu, Hu, Zhou, Yiting, Gao, Xiang, Lu, Linrong
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Biological Sciences; Catalysis; CD4 antigen; CD8 antigen; Cell activation; Cell lineage; Cell Proliferation; Cell Survival; Clonal deletion; Clonal selection; Dephosphorylation; Flox; Genes, p53; Lck protein; Lymphocytes; Lymphocytes T; Mass spectrometry; Mass spectroscopy; Maturation; Mice; Mice, Knockout; p53 Protein; Phosphatase; Phosphoprotein phosphatase; Phosphorylation; Positive selection; Protein phosphatase; Protein Phosphatase 2 - genetics; Protein Phosphatase 2 - metabolism; Proteins; Receptors, Antigen, T-Cell - metabolism; Signal Transduction; Substrates; Survival; T cell receptors; Thymocytes; Thymocytes - cytology; Thymocytes - enzymology; Thymus
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1821116116

The development of thymocytes to mature T cells in the thymus is tightly controlled by cellular selection, in which only a small fraction of thymocytes equipped with proper quality of TCRs progress to maturation. It is pivotal to protect the survival of the few T cells, which pass the selection. However, the signaling events, which safeguard the cell survival in thymus, are not totally understood. In this study, protein Ser/Thr phosphorylation in thymocytes undergoing positive selection is profiled by mass spectrometry. The results revealed large numbers of dephosphorylation changes upon T cell receptor (TCR) activation during positive selection. Subsequent substrate analysis pinpointed protein phosphatase 2A (PP2A) as the enzyme responsible for the dephosphorylation changes in developing thymocytes. PP2A catalytic subunit α (Ppp2ca) deletion in the T cell lineage in Ppp2ca flox/flox-Lck-Cre mice (PP2A cKO) displayed dysregulated dephosphorylation of apoptosis-related proteins in double-positive (DP) cells and caused substantially decreased numbers of DP CD4⁺ CD8⁺ cells. Increased levels of apoptosis in PP2A cKO DP cells were found to underlie aberrant thymocyte development. Finally, the defective thymocyte development in PP2A cKO mice could be rescued by either Bcl2 transgene expression or by p53 knockout. In summary, our work reveals an essential role of PP2A in promoting thymocyte development through the regulation of cell survival.